Kinetic cyclic ketones

For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored... 

The method can be further improved using trimethylsilyl (TMS) enol ethers, which can be prepared in situ from aldehydes and ketones [49]. TMS enol ethers of cyclic ketones are also suitable, and diversity can be enhanced by making either the kinetic or thermodynamic enol ether, as shown for benzyl methyl ketone. Thus, reaction of the kinetic TMS enol ether 10-133 with the amino aldehyde 10-134 and dimethylbarbituric acid 10-135 yielded 10-136, whereas the thermodynamic TMS enol ether 10-137 led to 10-138, again in excellent purity, simply by adding diethyl ether to the reaction mixture (Scheme 10.33). 

Kinetic resolution results of ketone and imine derivatives are indicated in Table 21.19. In the kinetic resolution of cyclic ketones or keto esters, ruthenium atrop-isomeric diphosphine catalysts 25 induced high enantiomer-discriminating ability, and high enantiopurity is realized at near 50% conversion [116, 117]. In the case of a bicyclic keto ester, the presence of hydrogen chloride in methanol served to raise the enantiomer-discriminating ability of the Ru-binap catalyst (entry 1) [116]. 

Dynamic kinetic resolution is possible for a-alkyl or a-alkoxy cyclic ketones in the presence of KOH, which causes mutation of the stereogenic center syn-alco-hols were obtained selectively with high enantioselectivity using ruthenium-3,5-xyl-binap. Dynamic kinetic resolution of 2-arylcycloalkanones also proceeded with extremely high syn-selectivity and with high enantioselectivity using ruthenium-binap-diamine as catalyst (Table 21.23) [12, 139, 140]. 

Bolm et al. (130) reported the asymmetric Baeyer-Villiger reaction catalyzed by Cu(II) complexes. Aerobic oxidation of racemic cyclic ketones in the presence of pivalaldehyde effects a kinetic resolution to afford lactones in moderate enan-tioselectivity. Aryloxide oxazolines are the most effective ligands among those examined. Sterically demanding substituents ortho to the phenoxide are necessary for high yields. Several neutral bis(oxazolines) provide poor selectivities and yields in this reaction. Cycloheptanones and cyclohexanones lacking an aryl group on the a carbon do not react under these conditions. 

A large number of studies have addressed the condensation of cyclic ketones with both aliphatic and aromatic aldehydes under conditions that reflect both thermodynamic (cf. Table 2) and kinetic control of stereochemistry. The data for cyclohexanone enolates are summarized in Table 8. Except for the boryl enolates cited (6), the outcome of the kinetic aldol process for these enolates... 

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

The enolates derived from cyclic ketones are necessarily. E-isomers. The enolate of cyclohexanone reacts with benzaldehyde to give both possible stereoisomeric products under kinetically controlled conditions. The stereochemistry can be raised to about 6 1 in favor of the anti isomer under optimum conditions.7 8... 

SCHEME 169. Chiral Pt complexes 231 employed as asymmetric inductors in the kinetic resolution of racemic cyclic ketones formed by enantioselective Baeyer-VilUger oxidation... 

The Baeyer-Villiger oxidation of cyclic ketones was also achieved by the MTO/H2O2 system in the ionic liquid [BMIM][BF4 [78] (Scheme23). Kinetic investigations have additionally been performed in order to follow the formation of the catalytically active peroxorhenium intermediates in the RTILs [81,82]. 

Bordeau and coworkers have described an efficient and stereoselective synthesis of kinetic silylenol ethers. Less highly substituted silylenolates are regiospecifically prepared in high yield, around room temperature under kinetic conditions, from unsymmetric cyclic ketones and [(DA)2Mg] in THF/heptane (equation 68). 

The course of hydrocarboxylation was studied further by sequential analyses of reaction mixtures and by detailed characterization of the purified carboxy acid products. Figure 1 plots kinetic runs with linoleic acid and methyl linoleate at 120°C. Analysis by GLC shows the rapid disappearance of diene followed successively by initial conjugation of the diene system, monocarboxylation, and then dicarboxylation. Cyclic ketones and other unidentified materials (not shown) are formed in minor amounts. Conjugated dienes (mixture of cis,trans and trans,trans) peak at 1 hr and then rapidly disappear. Monocarboxy acids peak around 6-8 hrs and disappear at later stages of the reaction. At 140°C, the carboxylation follows the same course (Figure 2A). Formation of conjugated dienes reach a maximum around 0.5 hr. Monocarboxy acids peak around 1 hr, decrease, and then level at 3-4 hrs. 

Figure 8 shows kinetic data on the catalytic hydrocarboxylation of methyl linolenate. There is initial conjugation of the triene system. Monocarboxy acids formed as initial products peak after 2 hrs and disappear almost completely. The dicarboxy acids are important intermediates and carboxylate further to give tricarboxy acids. The conversion to tricarboxy acids at 140°C does not exceed 50 to 53% (Runs 9 and 11, Table I). Cyclic ketones are formed as in linoleate in small but significant amounts. 

The kinetics of the oxidation of cyclic ketones by Caro s acid (peroxomonosulfuric acid, H2SO5) are first order in both, and the pH-rate profile has been analysed in terms of contributions from HSO5- and SOs2-.322 Similar results are found for aromatic aldehydes.323... 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

The problem of diastereoselective aldol addition has been largely solved48,108). Under kinetic control Z enolates favor erythro adducts and E enolates the threo diastereomers, although exceptions are known. This has been explained on the basis of a six-membered chair transition state in which the faces of the reaction partners are oriented so as to minimize 1,3 axial steric interactions 481108). This means that there is no simple way to prepare erythro aldols from cyclic ketones, since the enolates are geometrically fixed in the E geometry. 

Direct reaction of cyclic ketones with triethylgallium forms the kinetically-favored metal enolate without seeming complication from carbonyl addition. Conversely, triethyl-aluminum preferably gave the thermodynamically preferred hydride and ethyl addition products. 

In contrast with medium-sized cyclic ketones, alkylation of macrocyclic ketones can afford either optical antipode depending on whether the lithioenamine is formed via kinetic ( -) or thermodynamic conditions (Z-enamine) (eq 3). Optically active a-alkyl macrocyclic ketones have been formed in 30-82% enantiomeric... 

It was originally believed that the dissolving metal reduction of cyclic ketones would invariably afford the more stable of a pair of epimeric ketones as the major product. Although it has since been established beyond reasonable doubt that these reactions are kinetically controlled and that the less stable epimeric alcohol frequently predominates, the belief persists that these reductions are under thermodynamic control. ... 

A mechanistic interpretation of all the above facts would be attractive at this point. Unfortunately, a comprehensive explanation of the experimental results is not yet available, with die exception of kinetic studies on cyclic ketones and other carbonyls. ... 

Fortunately, the use of lithiated hydrazones derived from (S)- or ( )-l-amino-2-methoxymethylpyiro-lidine (SAMP or RAMP) as nucleophiles for asymmetric alkylations have provided a solution to the problems described above with metallated acyclic ketimines and aldimines. Lithiated SAMP or RAMP hydrazones of cyclic ketones are also alkylated in high yields. A major advantage of these chiral hydrazones is that their derivatives of aldehydes, acyclic and cyclic ketones all yield mainly ( )cc-. (Z)cN-Iithiated species on deprotonation with LDA in ethereal solvents under kinetic control. The ( )cc-configuration obtains as a result of the minimization of steric interactions in the usual closed transition... 

With ketones we come to the problem of regioselectivity, and the situation from chapter 3 is that methyl ketones 98 and ketones with one primary and one secondary alkyl group, particularly cyclic ketones such as 103 give the less substituted lithium enolate 97 or 102 by kinetically controlled deprotonation with LDA, and the more substituted silyl enol ether 99 or 104 on silylation under equilibrium conditions. Either derivative (lithium enolate or silyl enol ether) may be used to make the other, e.g. 96 and 100. 

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